Lens opacities can, of course, be associated with chromosomal aberrations, developmental conditions, intrauterine infections, and metabolic errors as well as single gene mutations. About 23% are familial but even among these there is considerable genetic and clinical heterogeneity that confounds the nosology despite notable recent progress in genotyping. Due to clinical heterogeneity, it is not always possible to classify specific families based on the appearance and natural history of the lens opacities alone.
Cerulean cataracts of congenital or childhood onset can be due to mutations in genes that encode various lens crystallins. Type 1 (CCA1; 115660) or ‘blue dot’ cerulean cataracts result from mutations in a gene located at 17q24 but its identity is as yet unknown. Intriguingly, it is located in the same chromosomal vicinity as the galactokinase deficiency gene (GALK1). The lens opacities are inherited as an autosomal dominant. This gene, however, does not appear to code for any of the major structural proteins of the lens.
Type 2 (CCA2; 601547) results from mutations in the CRYBB2 gene (22q11.2-q12.2) encoding the beta-B2-crystallin protein. Inheritance is autosomal dominant.
Type 3 (CCA3; 608983) is caused by mutations in CRYGD (2q33-q35) coding gamma-D-crystallin. It has been reported in a single family in which it seemed to appear earlier and progress more rapidly than other types. The pedigree pattern was consistent with autosomal dominant inheritance. Mutations in the same gene also cause an allelic disorder designated nonnuclear polymorphic congenital cataracts or PCC (601286), which may simply be clinical heterogeneity of the same condition.
Type 4 (CCA4; 610202) is due to mutations in the MAF gene (16q22-q23) and is also inherited in an autosomal dominant pattern. Lens opacities have a later, more juvenile onset and the lens opacities are located in a lamellar distribution in superficial cortical layers. These are progressive and often result in posterior subcapsular opacification that requires lens extraction in adults.
Type 5 (CCA5) is the result of a mutation in a locus at 12q24 and is dominantly inherited.
Other forms of autosomal dominantly inherited, congenital, progressive lens opacities include Volkmann type (115665), Coppock-like (604307), lamellar (116800), and congenital posterior polar (116600) cataracts.